All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
The current mainstay of treatment for type 1 diabetes (T1D) is insulin therapy, which has proven to be a lifesaving breakthrough. However, insulin treatment cannot fully prevent the severe complications related to the disease, including kidney failure and coronary heart disease. Successful islet transplantation can cure T1D, improve glycometabolic control, reduce hypoglycemic episodes, and halt diabetes complications. Unfortunately, the rate of functioning islet allografts at 5 years is well below 20%, primarily, although not exclusively, due to alloreactive and autoreactive immune responses. T cells recognize antigens through their T cell receptors (TCRs), which localize to the immune synapse and physically interact with peptides that are presented on MHC molecules by antigen-presenting cells (APCs). The anti-islet immune response involves a complex interplay between pathogenic and inflammatory immune pathways, which promote rejection, and regulatory or anti-inflammatory immune pathways, which facilitate tolerance toward transplants; one such pathway is the purinergic system. The purine ATP is a small molecule present at high concentrations within cells and released after cell damage or death and immune cell activation; it acts as a danger signal and potent chemotactic mediator. ATP is abundant at inflammation sites and is sensed by ionotropic purinergic P2X receptors (seven receptors named P2X1-P2X7, or P2XRs). P2X receptors can function as calcium channels, and autocrine activation of these receptors can facilitate calcium influx and downstream signaling. In leukocytes, P2XRs can regulate cytokine production, activation, and apoptosis, thus constituting an “autocrine alerting system”. In particular, P2X7R can serve as a signal amplification mechanism for antigen recognition. Thus, there is a need in the art for greater understanding of P2X receptors, as well as novel treatments for autoimmune related disorders, and development of more effective transplantation procedures.